| Project/Area Number |
17390227
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
SATA Masataka The University of Tokyo, Faculty of Medicine, Visiting Associate Professor, 医学部附属病院, 客員助教授 (80345214)
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| Co-Investigator(Kenkyū-buntansha) |
HIRATA Yasunobu The University of Tokyo, Faculty of Medicine, Associate Professor, 医学部附属病院, 助教授 (70167609)
ISHIZAKA Nobukazu The University of Tokyo, Faculty of Medicine, Assistant Professor, 医学部附属病院, 助教 (20270879)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,500,000 (Direct Cost: ¥15,500,000)
Fiscal Year 2006: ¥5,200,000 (Direct Cost: ¥5,200,000)
Fiscal Year 2005: ¥10,300,000 (Direct Cost: ¥10,300,000)
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| Keywords | Myocardial Infarction / Adventitia / Atherosclerosis / Blood Vessel / Tissue / Endothelial Cell / Angiogenesis / Inflammation / 粥腫 / プラーク / 急性冠症候群 / アンジオテンシン / 前駆細胞 |
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| Research Abstract |
Background : Accumulating evidence suggests that circulating progenitors potentially contribute to vascular healing and remodeling under physiological and pathological conditions. Although there is growing enthusiasm for therapeutic and diagnostic application of circulating progenitors, there are concerns that transplanted precursors or bone marrow-derived cells may participate in the pathogenesis of unfavorable diseases such as cancer, retinopathy, and atherosclerosis. Thus, it is warranted to clarify the molecular signaling that regulates the fate of circulating vascular progenitors. We investigated potential contribution of circulating blood cells in various types of vascular remodeling. We also studied the mechanical and humoral factors that recruit circulating progenitors to vascular lesions.
Methods and Results :
(1) We inserted a large wire into the femoral artery of wild-type mice whose bone marrow had been reconstructed with that of LacZ-mice expressing LacZ ubiquitously. The di
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lated lumen gradually narrowed due to neointimal hyperplasia, which was primarily composed of SMCs. A significant amount of neointimal and medial cells were LacZ-positive.
(2) We transplanted wild-type cardiac allografts into the wild-type mice whose bone marrow had been reconstituted with that of a LacZ-mouse or a GFP-mouse. At 4 weeks, we found that most of the neointimal cells were derived from the transplanted bone marrow.
(3) Peripheral mononuclear cells (MNCs) differentiated into α-SMA-positive cells in the presence of PDGF-BB and basic FGF. Contrary to the media-derived SMCs, the MNC-derived SMC-like cells expressed abundant MMP-9 and little collagen.
(4) The bone marrow of 59-week-old male ApoE-/- mice was replaced with that of an EGFP mouse. ApoE-/- mice at this age displayed established atherosclerotic plaques, in which SMCs and ECs frequently underwent apoptosis. After 34 weeks, more than 20% of the cells were found to be derived from bone marrow. There were bone marrow-derived EC-like cells that participated in re-endothelialization at luminal side and neovascularization at adventitia. Some of the EGFP positive cells expressed α-SMA or osteoblast-related proteins.
Conclusions : Our findings suggest that BM cells can give rise to vascular progenitor cells that home at the damaged vessels and differentiate into SMC-like cells or endothelial-like cells, thereby contributing to vascular repair, remodeling, and lesion formation. Our findings provide the basis for the development of new therapeutic strategies for vascular diseases, targeting mobilization, homing, differentiation and proliferation of bone marrow-derived vascular progenitor cells. Less
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